N-Boc-hydrazine

A novel synthesis of aza-/Mactams (Scheme 7.14) from the adducts of the reactions with N-Boc hydrazines 103 was recently reported by Naskar [53]. Thus, direct cyclization of 106 [52] with DIC gave 107, while participation in the Ugi reaction upon the addition of an aldehyde 109 and an isocyanide 110 gave more substituted derivatives 111 [53]. 

N-Amination. At low temperatures amines are transformed into N-Boc hydrazines by iV-(t-butoxycarbonyl)-3-trichloromethyloxaziridine. This reagent is superior to the 3-aryl analogs because by-product from the reaction is chloral which is water soluble and much more readily removed. 

Coupling of aryl halides and trifluoroacetamide occurred at 45-75 °C catalyzed by CuI/DMEDA (Lll), followed by in situ hydrolysis to provide the corresponding primary arylamines (entry 2) [32]. The Cul/l,10-phen (L13) catalytic system was found to be able to promote the selective coupling of N-Boc hydrazine [33] (entry 3) and the coupling of N- and O- functionalized hydroxylamines with aryl iodides (entry 4) [34]. Hosseinzadeh and coworkers reported the coupling reaction of aryl iodides with amides catalyzed by CuI/l,10-Phen (L13) by using KF/AI2O3 as the... 

Shibata and coworkers [135] described the asymmetric phase-transfer catalytic synthesis of trifluoromethyl-substituted 2-isoxazolines 100 by an enantioselective conjugate addition of hydroxylamine to trifluoromethylated enones 99 and subsequent intramolecular formation of the imine, whereas Briere et al. [136] developed a facile method for the straightforward enantioselective synthesis of 3,5-diaryl pyrazoHnes 102 by phase-transfer-catalyzed conjugate addition of N-Boc-hydrazine... 

The N " -BOC group can be removed under the usual conditions for removing the BOC group CF3COOH and HF. It can also be removed with hydrazine and NH3/ MeOH. NaOMe/MeOH/THF has been used to remove the BOC group from pyrroles in 66-99% yield. Thermolysis at 180° cleaves the BOC group from indoles and pyrroles in 92-99% yield. 

Whilst carbamate derivatives of indoles and pyrroles are easily prepared, they have limited synthetic utility because they are easily attacked by nucleophiles. For example, A -Aloc525 and A -Cbz526 derivatives of tryptophan are known, but they are destroyed by piperidine. Boc derivatives of indoles, pyrroles and imidazoles are sufficiently hindered to be synthetically useful For example, N-Boc indole is stable towards piperidine and it can be metallated in the 2-position with ferf-butyllithium.527 Nevertheless, they are still more easily cleaved by nucleophiles than Boc-derivatives of secondary amines as illustrated by the fact that Boc-derivatives of pyrrole are cleaved with sodium methoxide, ammonia or hydrazine in methanol527 In tryptophan derivatives, the Ar>w-Boc group is less susceptible to aridolysis than an Na-Boc group with trifluoroacetic acid. However, the M"-Boc group can be cleaved selectively by thermolysis as illustrated by a step in a synthesis of Asperazine [Scheme 8,271 ].52 ... 

Oxo-2-(trifluoromethyl)-4//-benzopyran-6-yl]methyl esters were proposed by Kemp and Hanson as a benzyl-like protecting group.After reaction of Boc amino acid cesium salts with the corresponding 6-(bromomethyl)-2-(trifluoromethyl)-4//-benzopyran-4-one esters are obtained in good yields. These esters can be used in Boc chemistry, since the N -Boc group can be cleaved in the presence of [4-oxo-2-(trifluoromethyl)-4//-benzopyran-6-yl]methyl esters. They are stable to secondary amines, but are cleaved by unhindered primary amines such as propylamine or dilute ethanolic hydrazine. 

Other nitrogen compounds, among them hydroxylamine and hydroxylamines, " hydrazines, and amides (15-9), also add to alkenes. Azodicarboxylates (Boc-N= N-Boc) react with alkenes, in the presence of PhSiH3 and a cobalt catalyst, to give... 

Scheme 10.3 Hydroarylation of bicyclic N-Boc protected hydrazines catalyzed by 54.

Furthermore, the allylated products were easily converted into the synthetically important N-Boc Q -amino esters as well as N-Boc a-amino ester hydrazine analogs without any loss of optical purity (Scheme 3.29). 

Compounds with an N-terminal protected azaamino acid residue can be produced by using acylated hydrazines, those with Boc and Z groups being favored. 319 Tosyl-protected compounds can likewise be prepared however, attempts to remove the tosyl protecting group using sodium in liquid ammonia were unsuccessful. 19 ... 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

The three orthogonally removable lysine protecting groups we use here are Fmoc (9-fluorenyl methoxy carbonyl), cleavable with 20% base, preferably with 20% piperidine or 3% DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) (18), Dde (1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl), cleavable with 2% hydrazine, and Aloe (allyloxy carbonyl), cleavable with palladium. Hydrazine also removes Fmoc, and thus it can be applied only if no Fmoc groups are present on the growing peptide chain. Acid-sensitive amino protecting groups available are Boc (tert-butyloxy carbonyl), cleavable with 90% TFA, and Mtt (4-methyl-trityl), cleavable with 1% TFA. We use Boc for the protection of the N-terminal moieties of N-terminal amino acids in each peptide chain as well as at the N-terminus of the scaffold. 

Protected peptides are cleaved from the resin with N-hydroxypiperidine (HOPip), followed by treatment with zinc in AcOH to afford the free acidJ Resin-bound peptides can be cleaved from the oxime resin using the tetrabutylammonium salts of side-chain protected amino acids to directly provide the a-amino-protected (Boc), side-chain-protected pep-tide.[ 3o- 32] Peptide esters can be obtained from peptidyl oxime resin by treating with amino acid estersJ Peptide hydrazides are derived from peptidyl oxime resins on treatment with anhydrous hydrazine.b Protected peptide amides can be also derived from peptidyl oxime resins on treatment with ammoniaJ l Cyclic peptide acids as carboxy components were successfully prepared by this procedure through the Pac ester. 

Camarero et al. [108] used the hydrazine safety-catch linker to prepare peptide thioesters. After assembling the peptide using standard Fmoc protocols, the fully protected peptide resin was activated by mild oxidation with N-bromosuc-cinimide (NB S) in the presence of pyridine, forming a reactive acyl diazene that was then deaved with an a-amino add S-alkyl thioester such as H-AA-SEt, where AA is Gly or Ala. After TFA deprotection, peptide thioesters were obtained in good yields. Although the oxidation step did produce racemization, and other sensitive amino acids such as Tyr(tBu) and Trp(Boc) were not affected, Met and Cys presented some problems. Met was completely oxidized, and a reductive cleavage was required. For Cys, the Cys(Trt) derivative should be avoided and use of Cys(Npys) or Cys(S-StBu) is recommended instead. 

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